Abstract
Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates β-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
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Acknowledgements
We are grateful to members of the Gleeson lab for technical expertise and feedback and the Nigam lab for helpful kidney-related discussions and reagents, as well as B. Brinkman and the UCSD Neuroscience Microscopy Core. We also thank the K. Kaushansky, M. Karin, and P.L. Mellon labs, as well as E.L. Stone for technical expertise. We are grateful to S. Piccolo at the Departments of Histology, Microbiology and Medical Biotechnologies, University of Padua, for the BATGAL mice. We thank S. Pleasure at the Department of Neurology, University of California–San Francisco, for Lrp6-mutant mice. We also thank M.G. Rosenfeld at the School of Medicine, UCSD, for the β-catΔN construct and R.T. Moon at the Department of Pharmacology, University of Washington, for the Super Topflash construct. M.A.L. and C.M.L received support from the US National Institutes of Health–National Institute of General Medical Sciences–funded UCSD Genetics Training Program (T32 GM08666). This work was supported by the US National Institutes of Health and the Burroughs Wellcome Fund in Translational Research (J.G.G.). J.G.G. is an investigator with Howard Hughes Medical Institute.
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M.A.L. designed the experimental approach, conducted the experiments and wrote the manuscript. J.G.G. supervised the project and experimental approach, interpreted data and contributed to manuscript preparation. C.M.L. designed and generated the Ahi1−/− mouse mutant and provided feedback. J.L.S. generated mutant constructs and assisted in microscopy. L.S. contributed to in vitro localization experiments. M.D. contributed to IRI experiments. S.K.N. provided feedback regarding renal characterization and manuscript preparation. K.W. provided feedback and reagents for in vitro Wnt assays.
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Lancaster, M., Louie, C., Silhavy, J. et al. Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat Med 15, 1046–1054 (2009). https://doi.org/10.1038/nm.2010
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DOI: https://doi.org/10.1038/nm.2010
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